Diagnostic method and diagnostic means used in delivering a medicament to a patient

ABSTRACT

The present invention relates to a diagnostic method used to indicate the migration of a medicament through the digestive apparatus and resorption during this migration, with the use of a negative MRI-contrast agent and a positive contract substance, introduced into gelatin capsules. The gelatin capsules are arranged as inner capsules in a common outer capsule, which is provided with barium sulphate in such an amount, relative to the specific gravity of the contents of the stomach, so that the capsule will be able to sink through the contents of the stomach and reach the small intestine without a substantial time-delay. The invention also relates to a diagnostic apparatus to carry out the diagnostic method.

FIELD OF THE INVENTION

The present invention relates to a diagnostic method and a diagnosticmeans used in carrying out the method.

In certain circumstances it is desirable but difficult to prove theexistence of a medicament in its surroundings in and on its way throughthe digestive apparatus.

Conventional methods use capsules, which are labeled with radioactiveisotopes. This certainly facilitates the finding of the capsule, but itsubjects the examined person to radiation, which should be avoided.

Another method tested, by means of magnetic resonance imaging (MRI),shows the existence of a tablet shown by a negative contrast agent (ironoxide+ barium) in the digestive apparatus, this tablet being shown as ablack silhouette against a white background of the conventional liquidpositive MRI-contrast agent Magnevist enteral.

This method has a drawback, since even if it is easy to visualize thisblack tablet in the ventricle (stomach) in a white sea of liquidcontrast agent, this very contrast agent, when being transferred to thesmall intestine, apparently is mixed with other digestive liquids, whichresults in an uneven, streaked filling of the small intestine, thetablet also being dissolved too quickly. Thus, an indication of theexistence of the tablet is not possible. Various efforts to make thepositive contrast agent more paste-like have not yielded anysatisfactory results. Examinations with Magnevist enteral and a negativecontrast agent, i.e. an agent which is black in an MRI-display, require,that the stomach is purged before the examinations.

U.S. Pat. No. 3,939,259 teach how to fill a capsule with tablets anddelay the release of medicaments by a layer of beeswax.

Barium sulphate and iron oxide in a water solution are used as negativecontrast agents according to U.S. Pat. No. 5,323,760.

WO 94/03210 relates to oils, used as positive contrast agents.

Various useful and also advantageous details are individually knownthrough these publications, but they are not combined in a particularway to speed up a diagnosis and make it more reliable, and so clear andsimple that certain preparatory measures, such as purging, completely orpartially can be dispensed with. Also no efforts apparently have beenspent to develop a simple, variable construction, which is easy to adaptto various diagnostic requirements and desires. Also, it has not beenfound, that so far there has been a generally expressed desire to designa capsule having tracer functions and which can be charged with anoptional module, which contains a substance to be examined.

The object of the present invention is to counteract and asfar-reachingly as possible overcome the above-mentioned drawbacks.Additional objects comprise the development of the state of the art inthis field in various respects.

These objects are achieved in accordance with the invention by designinga diagnostic method of the type described in the specification.

A negative MRI-contrast agent Abdoscan is on the market. This agent ismixed with water to a water solution, which, when it has been swallowed,becomes pudding-like in consistency in the digestive apparatus and fillse.g. the small intestine relatively uniformly, which substantiallyfacilitates the finding of the white signal capsule in this uniformblack sea of contrast agent. This is an obvious advantage compared tosaid liquid positive, i.e. white, contrast agents.

The following problem appeared; to develop a capsule, which through apositive contrast agent filling is clearly visible in a negativecontrast agent and which only in the lower part of the digestiveapparatus releases the substance to be examined and also is not toxic.This substance, i.e. the cargo portion, is allowed to be dissolveddepending on its composition, which varies from substance to substance,in interaction with the biochemical environments in the body in variousplaces along the movement path.

It has been found that certain deep-sea fish oil capsules on the marketyield an excellent positive contrast in MRI, i.e. gives a white picture.Other natural or synthetic organic non-toxic substances may also beused.

However, such capsules are dissolved too quickly, i.e. already in thestomach and also, they have the negative property in the stomach ofbeing lighter than water. Thus, they float on top of the contents of thestomach and do not reach the lower outlet of the stomach.

Consequently, two such capsules are wrapped in a mixture of iron oxide+barium sulphate powder in an empty gelatin capsule and two deep-sea fishoil capsules are chosen, since the signal picture which only one capsulegives, may look like the body's own structures, e.g. fat. In case theMRl-picture shows the two Inner capsules In front of each other, only abright white point is visible. In order to decide, whether this is thecapsule, the next picture is taken with a 90° angle in relation to theprevious one and then, In the same plane, two bright white points,having the same size, are visible, obviously a picture of the capsuleand not one of the body's own structures. In principle or alternatively,if is possible to choose such an oblong and/or a rectangular and/or anoval, inner capsule shape that, when said pictures are taken fromdifferent angles always at least one picture is obtained, which clearlydiffers from more common own structures of the body. As far as possible,in order to avoid taking pictures from different angles with greatreliability and speed are able to identify the position of the capsule,it is also possible to give the capsule an asymmetrical shape as regardsits contents in such a way, that one capsule side or end always tends tosink first, because this side or end contains substances having a largerweight and density, respectively. Alternatively, a small air inclusioncan serve the same purpose. An iron oxide is chosen due to the fact thatthis compound, because of its negative (black) MRI-picture, yields anincreased contrast around the positive (white) picture, whichsubstantially facilitates the determination of its position. Bariumsulphate is added because this compound substantially facilitates thedisplacement of the capsule through the force of gravity through thestomach and into the small intestine during the time when the patient,between the picture takings, is up and moves about. Tests without bariumsulphate have shown that the capsule then is too light-weight, flows ontop of the contents in the stomach and does not reach the smallintestine within several house. Also, barium sulphate has a negativecontrast effect, i.e. it gives a black picture in MRI.

Alternatively it is possible to put the signal substance in e.g. agelatin capsule, which is wrapped up in a shell, which consists of amixture of solid paraffin and barium sulphate.

It was found, that this functioned properly. An excellent contrast isseen between the two white oil capsules and the mixture of iron oxideand barium sulphate with its negative (black) MRI-picture and betweenthe positive substance and the signal-negative shell respectively, whichlatter consists of paraffin plus barium sulphate.

In the human body there are no structures, which yield such a similarsignal pattern in MRI, which substantially facilitates the finding ofthe capsule.

Also, the capsule is now so heavy, that it finds its way by itself tothe lower outlet of the stomach.

With regards to the dissolution which is too quick, beeswax does notmelt or is not dissolved at body temperatures. Thus, the dry gelatincapsule is provided on its outer side with liquid beeswax and has letthe beeswax cool. The capsule is still sufficiently heavy to sink,thanks to the included barium. However, thanks to the beeswax, it hasnot even been dissolved when it reaches the anal opening, which isperfect from the point of view that it then also is not able toinfluence the examination of the substance, which is to be examined.Instead of beeswax, it is possible to use a layer, which consists of amixture of solid paraffin (paraffinum solidum) and barium sulphate inorder to obtain a protection of the capsule and, at the same time, thebarium sulphate contributes to the necessary weight.

The substance to be examined is wrapped up in or is mixed with solidparaffin (paraffinum solidum). This solid paraffin portion constitutesthe cargo portion itself, i.e. that portion, which is optional and canbe united with the trace portion of the capsule. The release/dissolutiontakes place slowly or at a certain pH-value. It is done by coating thesubstance to be examined with a pH-sensitive substance. This method hasbeen tested during several decades by the pharmaceutical industry and isused by routine in certain pharmacological preparations. Thus, themethod allows a utilization of all this experience, how medicaments areto be mixed with paraffin in order to be released slowly andconsequently in a careful way, or put in another way, intentionallyduring a longer time in order to provide the same medicamentconcentration during a long time.

Instead of beeswax another non-toxic substance can be used, which meltsor dissolves only at higher temperatures than the temperatures of thebody, e.g. at 40-50° C., and which at least during a sufficiently longtime is able to resist the liquids in the body without dissolving in thewrong intestinal section and with that effect respectively, that it isdissolved in the proper intestinal section and also during a long time.

Tests have shown, that it is possible to indicate the capsule all theway from the stomach and through the entire small intestine and also inthe colon in its section close to the anal opening.

The present invention is not limited to what has been stated above,which only is to be considered a non-limiting embodiment, which can bemodified and supplemented in an arbitrary fashion within the scope ofthe inventive idea and the following claims respectively.

Instead of paraffin other substances can be used, e.g. waxes plusnon-toxic substances heavier than water instead of barium sulphate.

The substance to be examined can either be included in the outercapsule/the outer shell in the form of a separate capsule (the cargocapsule) or be mixed with the chemically inert substance of the shell.

It is found that a capsule, according to the invention, gives a clearsignal picture against the used contrast agent, that despite smallamounts of substances remaining in the stomach and the intestines, theotherwise mandatory purging before the examination is not required. Thisresults not only in a substantial relief for the patient, who avoids theinconvenience of having at least one day lost due to the purging, butalso in another advantage. A purging leads to an increased mobility inthe intestines. This increase mobility is a substantial drawback duringMRI-examinations, since the picture taking per se takes time (remindingone of the old-fashioned photographing, when it was necessary to standabsolutely still for a long period of time in order to obtain a shapepicture). However, it is not possible to stop the movement of theintestines by sheer willpower. On the other hand, the intestines holdsubstantially steady, if no purging is used and one keeps fasting fromthe evening before the examination and then in the morning swallows thecontrast agent and the capsule, which provides excellent, sharp picturesdespite certain small remaining amounts of substances in thestomach/intestines.

None of the other described diagnostic means has had any substantialmedical impact. None of them is said to be used commercially despite thefact, that these means have been known for several decades.

The invention will now be described, by way of example, with referenceto the accompanying drawings in which:

FIG. 1a is an inner capsule 1, which contains a positive contrastsubstance;

FIG. 1b is a lower portion 2 and upper portion 3 of a conventional outercapsule; in this example, only the lower portion is used as a n outercapsule;

FIG. 1c is an otherwise possible outer capsule, which consists of alower portion plus an upper portion;

FIG. 1d is an application of a first dose 4 of a heavy substance on thebottom of the lower portion, e.g. barium sulphate, possibly bariumsulphate and iron oxide;

FIG. 1e is an inner capsule, inserted in the lower portion, prepared inthis way, avoiding air inclusions. Alternatively, it is in this casepossible to form a possibly desirable small air inclusion in order tofacilitate a vertical positioning of the means in e.g. the stomach;

FIG. 1f is a second dose 5 of a heavy substance, applied on top of theinserted inner capsule;

FIG. 1g is a lower portion 6 of a second outer capsule, inserted withforced fit into the first lower portion, air inclusions being avoided;

FIG. 1h is a third dose 7 of a heavy substance, inserted into the secondlower portion;

FIG. 1i is a second inner capsule, inserted into the second lowerportion, prepared in this way;

FIG. 1j is a fourth dose 8 of a heavy substance, inserted into thesecond lower portion on top of the second inner capsule;

FIG. 1k is a thin layer 9 of liquid beeswax, applied to the outside ofthe construction, obtained in this way, and also to the inside from theoutside available portion of the second lower portion and to the freeoutside of said fourth dose 8;

FIG. 1l is a cargo portion 10, which consists of or contains asubstance, which is to be examined, which substance in a typical case isa drug substance, mixed with paraffin and is inserted into the open endof the second lower portion to fill this and be joined with its outerparaffin portions with the wax, which is still liquid; and

FIG. 1m is the border area between the wax layer and said paraffinportions, fused together in a way similar to how thermoplastic materialsfuse together. In this way some form of alloy or soldering together oradjacent portions is obtained and is guaranteed in a far-reaching way,that this entire construction is kept together up to the end, i.e. untilthis means has left the body. In order to facilitate the swallowing ofsaid means a part of the cargo portion, particularly the sides, whichare parallel to the lower portions, can be provided with a paraffinlayer 12, a soft transition zone between wax layer 9 and cargo portion10 being obtained. However, the rest of the outer side of the latter,particularly its outer free end 13, is not covered by the paraffinlayer, a dissolution, a leaching or the like in relation to presentliquids in the body being possible.

The present invention is not limited to the embodiments described aboveand/or shown in the accompanying drawings but can be modified andsupplemented in an arbitrary fashion within the scope of the inventiveidea and the following claims. Thus, barium sulphate and/or iron oxideare only to be regarded as examples. They can of course be replaced withother suitable substances, provided such substances are sufficientlyheavy and satisfactorily function as contrasting agents respectively.Also, the term capsule and capsules respectively can be replaced withother forms of enclosing/limiting means, e.g. various forms of coatingand/or treatment and filling respectively during a preferably fullyautomatic production process. By using a powdery substance or substancemixture the inner capsules will not be exposed to moisture. However, incase the material of the inner and outer capsules respectively isresistant to e.g. a water solution, which contains said heavy substanceand contrast agent respectively, it is of course possible to use such asolution instead to a powder.

What is claimed is:
 1. A method of delivering a medicament to adigestive tract of a patient to facilitate a magnetic resonance imagingdiagnosis of the patient's digestive tract, the method comprising thesteps of; filling at least one inner gelatin capsule with a first MRIcontrast agent; inserting the at least one inner gelatin capsule into anouter capsule; including the medicament with the outer capsule or in amaterial forming the outer capsule for release in the digestive tract;introducing the outer capsule and the at least one inner capsule into apatient's stomach; passing the outer capsule containing the at least oneinner capsule through the parent's stomach to a small intestine of thepatient faster than other contents of the patient's stomach; andemploying barium sulphate in the outer capsule as a second MRI contrastagent to facilitate the passing of the at least one inner capsulethrough the patient's stomach to the small intestine faster than theother contents of the stomach.
 2. The method of delivering a medicamentto a patent's digestive tract according to claim 1, further comprisingthe steps of; inserting iron oxide into the outer capsule as anadditional MRI contrast agent to facilitate distinguishing the at leastone inner gelatin capsule containing the first MRI contrast agent;providing a natural or synthetic organic non-toxic substance as thefirst MRI contrast agent; controlling the dissolution of the outercapsule and the release of the medicament by coating the outer capsulewith at least one of beeswax or a non-toxic substance having a meltingtemperature higher than a body temperature and which does not dissolvein contact with gastric stomach fluids of the patient's stomach.
 3. Themethod of delivering a medicament to a digestive tract of a patientaccording to claim 2, further comprising the step of forming the outercapsule from a mixture of solid paraffin and beeswax.
 4. The method ofdelivering a medicament to a digestive tract of a patient according toclaim 3, further comprising the steps of mixing the medicament with achemically inert substance and inserting the mixture into a cargocapsule attached to the outer capsule.
 5. The method of delivering amedicament to a digestive tract of a patient according to claim 4,further comprising the step of inserting at least two inner gelatincapsules into the outer capsule wherein so that when the at least twoinner capsules are observed from a desired angle the at least two innercapsules yield a noncircular or non-single point-shaped contrastingpicture.
 6. The method of delivering a medicament to a digestive tractof a patient according to claim 2, further comprising the step ofemploying deep sea fish oil as the natural or synthetic organicnon-toxic substance.
 7. The method of delivering a medicament to adigestive tract of a user according to claim 1, further comprising thestep of; introducing iron oxide into the outer capsule to enhance thevisual distinction between the first MRI contrast agent and the ironoxide in the outer capsule to improve detection in an MRI picture. 8.The method of delivering a medicament to a digestive tract of a patientaccording to claim 1, further comprising the step of at least one of theouter capsule and the inner capsule containing a mixture of solidparaffin and barium sulphate.
 9. The method of delivering a medicamentto a digestive tract of a patient according to claim 1, furthercomprising the step of binding at least one of the first, second andadditional MRI contrast agents by one of wax and paraffin, and formingat least one of the outer capsule and the at least one inner gelatincapsule from one of the wax and paraffin binding the at least one of thefirst, second and additional MRI contrast agents.